Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors
The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including mala...
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| Veröffentlicht in: | Cell chemical biology 2019-07, Vol.26 (7), p.991-1000.e7 |
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| creator | Schlott, Anja C Mayclin, Stephen Reers, Alexandra R Coburn-Flynn, Olivia Bell, Andrew S Green, Judith Knuepfer, Ellen Charter, David Bonnert, Roger Campo, Brice Burrows, Jeremy Lyons-Abbott, Sally Staker, Bart L Chung, Chun-Wa Myler, Peter J Fidock, David A Tate, Edward W Holder, Anthony A |
| description | The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance. |
| doi_str_mv | 10.1016/j.chembiol.2019.03.015 |
| format | Article |
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Advanced Photon Source (APS)</creatorcontrib><description>The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.</description><identifier>ISSN: 2451-9456</identifier><identifier>EISSN: 2451-9448</identifier><identifier>EISSN: 2451-9456</identifier><identifier>DOI: 10.1016/j.chembiol.2019.03.015</identifier><identifier>PMID: 31080074</identifier><language>eng</language><publisher>United States: Cell Press - Elsevier</publisher><subject>Acyltransferases - antagonists & inhibitors ; Acyltransferases - genetics ; Acyltransferases - metabolism ; Amino Acid Sequence ; antimalarial target ; Antimalarials - chemistry ; BASIC BIOLOGICAL SCIENCES ; crystal structure ; drug resistance development ; Enzyme Inhibitors - chemistry ; genetic manipulation ; Humans ; malaria ; Malaria, Falciparum - drug therapy ; myristoylation ; N-myristoyl ; Plasmodium ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - metabolism ; Polymorphism, Single Nucleotide - genetics ; post-translational modification ; protein lipidation ; Protein Processing, Post-Translational ; transferase</subject><ispartof>Cell chemical biology, 2019-07, Vol.26 (7), p.991-1000.e7</ispartof><rights>Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><rights>2019 The Authors 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-a5ff53753a080db175d66ca0163e84e7886dcb619203dc43a844b47371232bf63</citedby><cites>FETCH-LOGICAL-c441t-a5ff53753a080db175d66ca0163e84e7886dcb619203dc43a844b47371232bf63</cites><orcidid>0000-0001-6825-9404 ; 0000-0001-6753-8938 ; 0000-0002-6425-5577 ; 0000-0001-9570-5086 ; 0000-0002-2976-7374 ; 0000-0002-8490-6058 ; 0000-0002-0581-9387 ; 0000-0002-1600-4554 ; 0000-0002-6090-1877 ; 0000-0003-2561-6648 ; 0000-0003-2213-5814 ; 0000-0002-7139-8699 ; 0000-0002-0056-0513 ; 0000-0001-8448-6068 ; 0000-0002-2480-3110 ; 0000000271398699 ; 0000000229767374 ; 0000000264255577 ; 0000000205819387 ; 0000000224803110 ; 0000000260901877 ; 0000000184486068 ; 0000000195705086 ; 0000000325616648 ; 0000000284906058 ; 0000000167538938 ; 0000000216004554 ; 0000000200560513 ; 0000000322135814 ; 0000000168259404</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27915,27916</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31080074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1544855$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Schlott, Anja C</creatorcontrib><creatorcontrib>Mayclin, Stephen</creatorcontrib><creatorcontrib>Reers, Alexandra R</creatorcontrib><creatorcontrib>Coburn-Flynn, Olivia</creatorcontrib><creatorcontrib>Bell, Andrew S</creatorcontrib><creatorcontrib>Green, Judith</creatorcontrib><creatorcontrib>Knuepfer, Ellen</creatorcontrib><creatorcontrib>Charter, David</creatorcontrib><creatorcontrib>Bonnert, Roger</creatorcontrib><creatorcontrib>Campo, Brice</creatorcontrib><creatorcontrib>Burrows, Jeremy</creatorcontrib><creatorcontrib>Lyons-Abbott, Sally</creatorcontrib><creatorcontrib>Staker, Bart L</creatorcontrib><creatorcontrib>Chung, Chun-Wa</creatorcontrib><creatorcontrib>Myler, Peter J</creatorcontrib><creatorcontrib>Fidock, David A</creatorcontrib><creatorcontrib>Tate, Edward W</creatorcontrib><creatorcontrib>Holder, Anthony A</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors</title><title>Cell chemical biology</title><addtitle>Cell Chem Biol</addtitle><description>The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.</description><subject>Acyltransferases - antagonists & inhibitors</subject><subject>Acyltransferases - genetics</subject><subject>Acyltransferases - metabolism</subject><subject>Amino Acid Sequence</subject><subject>antimalarial target</subject><subject>Antimalarials - chemistry</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>crystal structure</subject><subject>drug resistance development</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>genetic manipulation</subject><subject>Humans</subject><subject>malaria</subject><subject>Malaria, Falciparum - drug therapy</subject><subject>myristoylation</subject><subject>N-myristoyl</subject><subject>Plasmodium</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - metabolism</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>post-translational modification</subject><subject>protein lipidation</subject><subject>Protein Processing, Post-Translational</subject><subject>transferase</subject><issn>2451-9456</issn><issn>2451-9448</issn><issn>2451-9456</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctOAjEYhRujEYK8Apm4n7GdXmbYmCBRJEFNvKybTqcDxaElbTFh5yv4ij6JJQjRVZv0nNPz_x8AAwQzBBG7WmZyoVaVtm2WQzTMIM4goiegmxOK0iEh5enxTlkH9L1fQhiduEC4OAcdjGAJYUG6YP4S3EaGjVPpZKNrVSfTWpmgGy1F0NYktkmeldc-CCNVcuOUeNdmnoyiZiVa4bRok8fvz6-HrYsiu22DE8Y3ygmvkqlZ6EoH6_wFOGtE61X_9-yBt7vb1_F9OnuaTMejWSoJQSEVtGkoLigWsWBdoYLWjEmxq65KooqyZLWsGBrmENeSYFESUpEizpXjvGoY7oHrfe56U61ULeMsTrR87WJbt-VWaP7_xegFn9sPzhgtGSpiwOU-wPqguZc6KLmQ1hglA0c07pbSKGJ7kXTWe6ea4wcI8h0ivuQHRHyHiEPMI6JoHPytd7QdgOAf0qKTTA</recordid><startdate>20190718</startdate><enddate>20190718</enddate><creator>Schlott, Anja C</creator><creator>Mayclin, Stephen</creator><creator>Reers, Alexandra R</creator><creator>Coburn-Flynn, Olivia</creator><creator>Bell, Andrew S</creator><creator>Green, Judith</creator><creator>Knuepfer, Ellen</creator><creator>Charter, David</creator><creator>Bonnert, Roger</creator><creator>Campo, Brice</creator><creator>Burrows, Jeremy</creator><creator>Lyons-Abbott, Sally</creator><creator>Staker, Bart L</creator><creator>Chung, Chun-Wa</creator><creator>Myler, Peter J</creator><creator>Fidock, David A</creator><creator>Tate, Edward W</creator><creator>Holder, Anthony A</creator><general>Cell Press - Elsevier</general><general>Cell Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6825-9404</orcidid><orcidid>https://orcid.org/0000-0001-6753-8938</orcidid><orcidid>https://orcid.org/0000-0002-6425-5577</orcidid><orcidid>https://orcid.org/0000-0001-9570-5086</orcidid><orcidid>https://orcid.org/0000-0002-2976-7374</orcidid><orcidid>https://orcid.org/0000-0002-8490-6058</orcidid><orcidid>https://orcid.org/0000-0002-0581-9387</orcidid><orcidid>https://orcid.org/0000-0002-1600-4554</orcidid><orcidid>https://orcid.org/0000-0002-6090-1877</orcidid><orcidid>https://orcid.org/0000-0003-2561-6648</orcidid><orcidid>https://orcid.org/0000-0003-2213-5814</orcidid><orcidid>https://orcid.org/0000-0002-7139-8699</orcidid><orcidid>https://orcid.org/0000-0002-0056-0513</orcidid><orcidid>https://orcid.org/0000-0001-8448-6068</orcidid><orcidid>https://orcid.org/0000-0002-2480-3110</orcidid><orcidid>https://orcid.org/0000000271398699</orcidid><orcidid>https://orcid.org/0000000229767374</orcidid><orcidid>https://orcid.org/0000000264255577</orcidid><orcidid>https://orcid.org/0000000205819387</orcidid><orcidid>https://orcid.org/0000000224803110</orcidid><orcidid>https://orcid.org/0000000260901877</orcidid><orcidid>https://orcid.org/0000000184486068</orcidid><orcidid>https://orcid.org/0000000195705086</orcidid><orcidid>https://orcid.org/0000000325616648</orcidid><orcidid>https://orcid.org/0000000284906058</orcidid><orcidid>https://orcid.org/0000000167538938</orcidid><orcidid>https://orcid.org/0000000216004554</orcidid><orcidid>https://orcid.org/0000000200560513</orcidid><orcidid>https://orcid.org/0000000322135814</orcidid><orcidid>https://orcid.org/0000000168259404</orcidid></search><sort><creationdate>20190718</creationdate><title>Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors</title><author>Schlott, Anja C ; Mayclin, Stephen ; Reers, Alexandra R ; Coburn-Flynn, Olivia ; Bell, Andrew S ; Green, Judith ; Knuepfer, Ellen ; Charter, David ; Bonnert, Roger ; Campo, Brice ; Burrows, Jeremy ; Lyons-Abbott, Sally ; Staker, Bart L ; Chung, Chun-Wa ; Myler, Peter J ; Fidock, David A ; Tate, Edward W ; Holder, Anthony A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-a5ff53753a080db175d66ca0163e84e7886dcb619203dc43a844b47371232bf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acyltransferases - antagonists & inhibitors</topic><topic>Acyltransferases - genetics</topic><topic>Acyltransferases - metabolism</topic><topic>Amino Acid Sequence</topic><topic>antimalarial target</topic><topic>Antimalarials - chemistry</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>crystal structure</topic><topic>drug resistance development</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>genetic manipulation</topic><topic>Humans</topic><topic>malaria</topic><topic>Malaria, Falciparum - drug therapy</topic><topic>myristoylation</topic><topic>N-myristoyl</topic><topic>Plasmodium</topic><topic>Plasmodium falciparum - drug effects</topic><topic>Plasmodium falciparum - metabolism</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>post-translational modification</topic><topic>protein lipidation</topic><topic>Protein Processing, Post-Translational</topic><topic>transferase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schlott, Anja C</creatorcontrib><creatorcontrib>Mayclin, Stephen</creatorcontrib><creatorcontrib>Reers, Alexandra R</creatorcontrib><creatorcontrib>Coburn-Flynn, Olivia</creatorcontrib><creatorcontrib>Bell, Andrew S</creatorcontrib><creatorcontrib>Green, Judith</creatorcontrib><creatorcontrib>Knuepfer, Ellen</creatorcontrib><creatorcontrib>Charter, David</creatorcontrib><creatorcontrib>Bonnert, Roger</creatorcontrib><creatorcontrib>Campo, Brice</creatorcontrib><creatorcontrib>Burrows, Jeremy</creatorcontrib><creatorcontrib>Lyons-Abbott, Sally</creatorcontrib><creatorcontrib>Staker, Bart L</creatorcontrib><creatorcontrib>Chung, Chun-Wa</creatorcontrib><creatorcontrib>Myler, Peter J</creatorcontrib><creatorcontrib>Fidock, David A</creatorcontrib><creatorcontrib>Tate, Edward W</creatorcontrib><creatorcontrib>Holder, Anthony A</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). 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Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors</atitle><jtitle>Cell chemical biology</jtitle><addtitle>Cell Chem Biol</addtitle><date>2019-07-18</date><risdate>2019</risdate><volume>26</volume><issue>7</issue><spage>991</spage><epage>1000.e7</epage><pages>991-1000.e7</pages><issn>2451-9456</issn><eissn>2451-9448</eissn><eissn>2451-9456</eissn><abstract>The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. 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| fulltext | fulltext |
| identifier | ISSN: 2451-9456 |
| ispartof | Cell chemical biology, 2019-07, Vol.26 (7), p.991-1000.e7 |
| issn | 2451-9456 2451-9448 2451-9456 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6658617 |
| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Acyltransferases - antagonists & inhibitors Acyltransferases - genetics Acyltransferases - metabolism Amino Acid Sequence antimalarial target Antimalarials - chemistry BASIC BIOLOGICAL SCIENCES crystal structure drug resistance development Enzyme Inhibitors - chemistry genetic manipulation Humans malaria Malaria, Falciparum - drug therapy myristoylation N-myristoyl Plasmodium Plasmodium falciparum - drug effects Plasmodium falciparum - metabolism Polymorphism, Single Nucleotide - genetics post-translational modification protein lipidation Protein Processing, Post-Translational transferase |
| title | Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors |
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